Hypoxia-driven M2-polarized macrophages facilitate the epithelial-mesenchymal transition of glioblastoma via extracellular vesicles.

in Theranostics by Liang Liu, Ran Wang, Aogesi Alifu, Yong Xiao, Yong Liu, Chunfa Qian, Mengjie Zhao, Xianglong Tang, Yandong Xie, Yan Shi, Yuanjie Zou, Hong Xiao, Kun Yang, Hongyi Liu

TLDR

  • The study investigates how a type of immune cell called macrophages can help cancer cells grow and spread in the brain. The study found that a type of macrophage called M2-like TAMs can help cancer cells grow and spread by transporting a molecule called circ_0003137 to the cancer cells. The study also found that a type of protein called PTBP1 helps to keep this molecule stable, which helps the cancer cells to grow and spread. The study also found that a type of protein called PLOD3 helps to make the molecule that the cancer cells need to grow and spread. The study also found that a type of nanoparticle called a liposome can be used to deliver a type of protein called shRNA to the cancer cells to stop them from growing and spreading. The study also found that the nanoparticle can penetrate the blood-brain barrier, which is a protective layer around the brain, to reach the cancer cells. The study also found that the nanoparticle can significantly inhibit the growth and spread of the cancer cells in the brain. The study suggests that targeting circ_0003137 and PTBP1/PLOD3 might be a novel therapeutic strategy against glioblastoma.

Abstract

M2-like tumor-associated macrophages (TAMs) promote the malignant progression of glioblastomas. However, the mechanisms responsible for this phenomenon remain unclear.RT-PCR, Western blot and flow cytometry were used to evaluate the polarization status of macrophages. RT-PCR, western blot or/and immunohistochemistry was used to determine the expression of circ_0003137, PTBP1, PLOD3 and epithelial-mesenchymal transition (EMT) markers. Transwell assay was used to assess migration and invasion ability of tumor cells. RNA sequencing, bioinformatic analysis and Pearson correlation coefficient was performed to explore the relation between PTBP1 and circ_003137/PLOD3.experiment was used to determine the role of sh-circ_0003137-loaded nanoplatform.Hypoxia promoted the polarization of macrophages towards M2-like TAMs in an HIF1α dependent manner. Then, M2-like TAMs could transport circ_0003137 enriched extracellular vesicles (EVs) to glioblastoma cells, upregulating circ_0003137 in glioblastoma cells. The circ_0003137 overexpression promoted the EMT of glioblastoma cellsand. Mechanistically, circ_0003137 physically binds to polypyrimidine tract binding protein 1 (PTBP1), enhancing the stability of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and promoting the EMT of glioblastoma cells. Moreover, a liposome-based nanoplatform that delivers shRNAs was established and used to encapsulate sh-circ_0003137. The fluorescence microscope tracer and cell co-culture assays demonstrated that the nanoplatform encapsulated with sh-circ_0003137 was stable and could penetrate the blood-brain barrier (BBB), finally reaching the central nervous system (CNS). The intracranialtumor model showed that injecting the sh-circ_0003137-loaded nanoplatform via the tail vein significantly inhibited glioblastoma progression and improved the nude mice's survival.Hypoxia can drive macrophage polarization towards M2-like TAMs. Polarized M2-like TAMs can transport circ_0003137 to glioblastoma cells through EVs. Then, circ_0003137 promotes the EMT of glioblastomas by targeting the PTBP1/PLOD3 axis. Hence, targeting circ_0003137 might be a novel therapeutic strategy against glioblastoma.

Overview

  • The study investigates the role of M2-like tumor-associated macrophages (TAMs) in promoting the malignant progression of glioblastomas. The study uses RT-PCR, Western blot, flow cytometry, RNA sequencing, bioinformatic analysis, and Pearson correlation coefficient to evaluate the polarization status of macrophages, the expression of circ_0003137, PTBP1, PLOD3, and EMT markers, and the relation between PTBP1 and circ_003137/PLOD3. The study also uses a liposome-based nanoplatform to deliver shRNAs to target circ_0003137 and evaluate its effect on glioblastoma progression and survival in an intracranial tumor model.

Comparative Analysis & Findings

  • The study found that hypoxia promoted the polarization of macrophages towards M2-like TAMs in an HIF1α dependent manner. Then, M2-like TAMs could transport circ_0003137 enriched extracellular vesicles (EVs) to glioblastoma cells, upregulating circ_0003137 in glioblastoma cells. The circ_0003137 overexpression promoted the EMT of glioblastoma cells. Mechanistically, circ_0003137 physically binds to polypyrimidine tract binding protein 1 (PTBP1), enhancing the stability of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and promoting the EMT of glioblastoma cells. The study also found that a liposome-based nanoplatform that delivers shRNAs was stable and could penetrate the blood-brain barrier (BBB), finally reaching the central nervous system (CNS). The intracranial tumor model showed that injecting the sh-circ_0003137-loaded nanoplatform via the tail vein significantly inhibited glioblastoma progression and improved the nude mice's survival.

Implications and Future Directions

  • The study highlights the importance of M2-like TAMs in promoting glioblastoma progression and suggests that targeting circ_0003137 might be a novel therapeutic strategy against glioblastoma. The study also identifies the PTBP1/PLOD3 axis as a potential therapeutic target for glioblastoma. Future research could further explore the mechanisms underlying the PTBP1/PLOD3 axis and the role of M2-like TAMs in glioblastoma progression. Additionally, future research could investigate the safety and efficacy of using nanoparticles to deliver shRNAs for the treatment of glioblastoma.
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